[Mark11]

New York Times article on immunotherapy

by Mark11 on Mon Aug 01, 2016 8:02 am

The New York Times on Saturday published a good article on immunotherapy for cancer:

"Harnessing the Immune System to Fight Cancer," New York Times, July 30, 2016(full text of article)

Check down the right hand side for more links to related articles. These are good articles dealing with the reality of immunotherapy.

Here's an excerpt from Saturday's article:

"If there is a potential downside to the advances, Dr. Hellmann said, it is that the buzz about immunotherapy has led some patients to think chemotherapy is passé.

“Immunotherapy represents a hugely important new tool, but chemotherapy can work too and has been the backbone of the way we’ve treated patients with lung cancer,” he said. “Immunotherapy is not a replacement for that. It’s a new weapon.”

One of his patients, a 60-year-old man with lung cancer that had spread to his brain, was eager to try immunotherapy instead of chemotherapy. After having radiation treatment for one brain tumor, he began treatment with two checkpoint inhibitors.

But they did not work. So his doctors switched to chemotherapy. “He’s had a tremendous response,” Dr. Hellmann said.

He said it was impossible to tell whether the immunotherapy could have had some delayed effect and worked synergistically with the chemotherapy. Clinical trials are now trying to resolve that question.

But the potential for dangerous side effects cannot be overemphasized, doctors say. A 2010 article in a medical journal reported that a few melanoma patients had died from adverse effects of Yervoy.

In addition to causing lung inflammation, checkpoint inhibitors can lead to rheumatoid arthritis and colitis, a severe inflammation of the intestine – the result of an attack by the revved-up immune system that over-the-counter remedies cannot treat. Patients need steroids like prednisone to quell these attacks. Fortunately – and mysteriously, Dr. Wolchok said – the steroids can halt the gut trouble without stopping the immune fight against the cancer. But if patients delay telling doctors about diarrhea, Dr. Wolchok warned, “they could die” from colitis."

[JPC]

Re: New York Times article on immunotherapy

by JPC on Mon Aug 01, 2016 9:23 am

Saw that too.

Interestingly, as others have observed from time to time, novel treatments, in this case immunotherapy, are not entirely new. Dr. William Coley had some interesting results at Sloan Kettering in New York going back to 1891. His approach came to be known as "Coley's toxins". It did actually achieve impressive responses for the day. However, based on the technology of the day, he was not able to develop it to have across-the-board performance, only isolated successes.

As radiation and chemotherapy came along, those approaches performed better than Coley's toxins. Of great interest, however, when they could not figure out how to improve Coley's approach, and the new philosophies came to overtake his approach, the medical community discredited him, and some labeled it a "quack" approach.

In fact, Dr. Coley was way ahead of his time. Hopefully, this time around, with more advanced biological science and DNA knowledge, they will do a better job at figuring it out.

[mikeb]

Re: New York Times article on immunotherapy

by mikeb on Tue Aug 02, 2016 11:43 pm

Thanks, Mark11, for letting us know about this article. It seems like a good overview of immunotherapy. And articles yesterday and today have explained monoclonal antibodies and CAR-T therapy. All are good reading for people who want to learn more about this area of treatment, explained in a way that we regular folks can understand.

Reading and thinking about immunotherapy over the past few days leads me to a (perhaps dumb) question. Are Revlimid and Pomalyst considered to be immunotherapy? I know they are immunomodulatory agents, but I never see them mentioned when I read about immunotherapy. If they are not, then what's the difference between immunomodulatory agents and immunotherapy agents?

Mike

[JPC]

Re: New York Times article on immunotherapy

by JPC on Wed Aug 03, 2016 4:11 pm

Hi Mike:

I am not knowledgeable enough to give you a real technically sound scientific answer (that has not stopped me before), but here is an observation that I recall from what I've heard and read.

The body's immune components are: white blood cells, T-cells, NK cells, and immunoglobulins. They "see" foreign agents in the blood and tissue by "looking" at them. That is to say their surface characteristics. They "attack" the bad cells (i.e., the pathogens) by reacting with targets on the surface of the cells. The monoclonal antibodies attack the surface of the myeloma cells, like the body's immune system.

The drugs, novel agents and chemotherapy agents, have a means of action of being absorbed into the cells, and work from the inside out, via bio-chemical reactions. Thalidomide, Revlimid, and Pomalyst are drugs that have the closest effect to immunotherapies, but they still fall on the side of "drug" interactions, by being absorbed into the cells, rather than attacking the multiple myeloma via its surface. In fact, the IMID's, I understand, have a means of action that TENDS TO kill (some, not all) the multiple myeloma cells, however the effect on the rest of the immune system is somewhat to suppress the immune activity, not stimulate it.

Good luck.

[Mark11]

Re: New York Times article on immunotherapy

by Mark11 on Thu Aug 04, 2016 9:22 am

I agree with JPC that Revlimid is probably more of a drug than immunotherapy. I just wanted to make comment on the last sentence:

"In fact, the IMID's, I understand, have a means of action that TENDS TO kill (some, not all) the multiple myeloma cells, however the effect on the rest of the immune system is somewhat to suppress the immune activity, not stimulate it."

Take note that immunotherapy can lead to a suppressed immune system. Note that patients that use CD19 directed CAR T cells that have long-term remission typically (always?) are left without healthy B cells. Note what is written about 2 of the success stories in this article:

"Side Effects: Lung problems, swelling, low blood pressure in days following the treatment. Now: prone to infection because B cells are depleted, so needs periodic infusions of immunoglobulin."

"Side Effects: Severe immune system reaction with high fever, as well as temporary trouble thinking in the days after treatment. Now, prone to infection and takes prophylactic antibiotics and periodic immunoglobulin."

Needing IVIG is a sign of having a poorly functioning immune system.

I had posted this link in another thread. It is an article about Darzalex. At the end of the article, the authors mention the key to a durable, curative response from immunotherapy for patients.

"An overdue era of immune therapy in multiple myeloma has begun, and the prospect of triggering LONG-TERM MEMORY anti-multiple myeloma immunity in patients at early stages of disease offers great potential for prolonged survival and potential cure."

Reference: Tai, Y, and Anderson, K.C., "A new era of immune therapy in multiple myeloma," Blood, 2016 (full text of article)

Based on the fact that most all patients relapse while using maintenance with the current, widely used myeloma therapies, it is clear they are not providing what is mentioned above.

[mikeb]

Re: New York Times article on immunotherapy

by mikeb on Fri Aug 05, 2016 5:38 pm

Thanks, JPC and Mark11, for your replies to my question.

Basically my question was one of semantics, and I probably could have stated it better if I had made that clearer. Are immunomodulatory agents considered to be a sub-class of immuno­therapy?

Both of your responses help clear that up a bit. It seems like you're in agreement that Revlimid, for example, is, as Mark said, "more of a drug than immunotherapy."

I had my monthly checkup Wednesday, so I took that opportunity to ask my doctor at Memorial Sloan Kettering (Dr. Alexander Lesokhin) about this. His short answer was, "Yes, Revlimid is considered to be immunotherapy, by people who are not immunologists."

You've got to understand his sense of humor to get this – his specialty is, in fact, immunology – so this was his way of saying, "No."

We got into a deeper discussion about IMiDs' methods of action and that helped me understand the distinction better, but I certainly still don't understand it completely. I'll try to summarize our discussion here.

Revlimid alters production of some cytokines, reducing production of TLF-alpha and IL-6 (pro-inflammatory cytokines) and increasing the production of IL-10 (an anti-inflammatory cytokine). The pro-inflammatory cytokines seem to be important for myeloma cell growth, while anti-inflammatory cytokines may help with tumor apoptosis (death).

Dr. Lesokhin's point here was that while cytokines are part of the immune system, their activation by a drug is not enough for that drug to be considered immunotherapy by immunologists.

He also pointed out that IMiDs also stimulate T-cell production. That (or some form of T-cell involvement) is more of a key factor that's necessary for "immunotherapy." But in Revlimid's case (and I assume thalidomide and Pomalyst too), according to Dr. Lesokhin, it is not clear how or even whether the stimulated T-cells actually work against myeloma.

In addition, IMiDs also seem to indirectly increase the production of NK (Natural Killer) cells, but that mechanism with respect to IMiDs and myeloma does not seem to be well understood either.

So there's sort of a grey area with regard to T-cells and NK cells. And, if I understood Dr. Lesokhin correctly, their activation and action against tumors is necessary for an agent to be considered "immunotherapy." I think Mark11's point about memory is important here too, and T-cells (as I understand it) would be where that "memory" is held.

Also, Revlimid has anti-angiogenesis properties (reducing the development of blood vessels); that's another way that it works against myeloma cells.

So ... that's my interpretation of what Dr. Lesokhin said in relation to this question. I hope I'm not too far off base. I can only imagine him shaking his head if he reads this.

I ran across a decent journal article explaining the different anti-tumor properties of IMiDs. If you're curious for more information, this might be a good resource:

Kotla V., et. al., "Mechanism of action of lenalidomide in hematological malignancies," Journal of Hematology & Oncology, 2009, 2:36 (full text of article)

And, finally, to clarify something. JPC said, "The body's immune components are: white blood cells, T-cells, NK cells, and immunoglobulins." I'm not sure if you meant it this way, but that wording implies that T-cells and NK cells are NOT white blood cells. T-cells and NK cells (along with B-cells) are lymphocytes, one type of white blood cell. The Wikipedia article on white blood cells does a pretty good job of explaining the categories and sub-categories of white blood cells.

Mike

[JPC]

Re: New York Times article on immunotherapy

by JPC on Fri Aug 05, 2016 6:14 pm

Hello Mike:

Thank you for the excellent response. I was trying to sprout some blather on "the internet". You however, went maybe 90% of the way to publishing an article in a leading learned journal.

To answer your question, I did not MEAN to say that different types of white blood cells were something different (a sub-class), but I think you are correct as to what I DID in fact say. So thank you for the clarification.

But in a simplistic point of view without getting into the deep biochemistry (which I am not qualified to do), I do have the under­stand­ing that drugs work inside the cells (on the complicated bio­chemical inner cellular processes), but immunotherapy works on the "surface" of the cells. I may have to read your article numerous times (and I will) to grasp it, but somehow I think that Dr. Leshotkin's comments are consistent with that concept
.
Taking the point one step further, since immunotherapy operates by a completely different modality, incorporating immunotherapy agents (Darzalex, Empliciti, Tecentriq, Keytruda, etc) could potentially have synergistic impacts with the "novel agents" for great benefit for most multiple myeloma patients (some researchers speculate), greatly extending deeper responses and longer remissions.

[mikeb]

Re: New York Times article on immunotherapy

by mikeb on Sat Aug 06, 2016 11:42 am

Thanks for your reply to my post, JPC. And thanks for the kind comment about it. Trying to write down what I thought I heard Dr. Lesokhin say helped me to sort of consolidate it in my own head.

I was thinking some more about the distinction Dr. Lesokhin made between how immuno­modu­latory agents work and how immunotherapy agents work. I don't think I answered that question directly in my post because, unfortunately, I'm not completely clear on the distinction.

You may be right in your suggestion that the distinction is over whether the agents work inside the cell vs. on the surface (if I'm understanding what you're saying correctly). But I'm not sure about that.

Another distinction Dr. Lesokhin seemed to be making is that immunotherapy agents must modify the immune system in some way and then the immune system does the work of attacking myeloma cells. But I'm not so sure whether I've got that right or not. When Revlimid stimulates the production of cytokines, that's modifying the immune system since cytokines are part of the immune system.

Maybe there's a distinction between "lasting" changes to the immune system, like T-cell changes, and more temporary changes like producing cytokines. I don't know.

The more I learn, the more I realize how much I don't know!

Mike

[Mark11]

Re: New York Times article on immunotherapy

by Mark11 on Wed Aug 10, 2016 9:09 am

Hi MikeB,

You wrote:

I had my monthly checkup Wednesday, so I took that opportunity to ask my doctor at Memorial Sloan Kettering (Dr. Alexander Lesokhin) about this. His short answer was, "Yes, Revlimid is considered to be immunotherapy, by people who are not immunologists."

That is funny. My doctor is the same way. As a side note, all we ever talk about with regard to myeloma/blood cancer is how the immune system can eliminate cancer. I see my doctor at least 3 times per year currently and we have never discussed Kyprolis or Pomalyst but we are constantly discussing things like T and NK cells.

Another point I would make is that all drugs that we use could be considered immuno­modu­latory agents. Take cyclophosphamide (an alkylator) for instance.

"Drug repositioning refers to the utilization of a known compound in a novel indication underscoring a new mode of action that predicts innovative therapeutic options. Since 1959, alkylating agents, such as the lead compound cyclophosphamide (CTX), have always been conceived, at high dosages, as potent cytotoxic and lymphoablative drugs, indispensable for dose intensity and immunosuppressive regimen in the oncological and internal medicine armamentarium. However, more recent work highlighted the immunostimulatory and/or antiangiogenic effects of low dosing CTX (also called "metronomic CTX") opening up novel indications in the field of cancer immunotherapy. CTX markedly influences dendritic cell homeostasis and promotes IFN type I secretion, contributing to the induction of antitumor cytotoxic T lymphocytes and/or the proliferation of adoptively transferred T cells, to the polarization of CD4(+) T cells into TH1 and/or TH17 lymphocytes eventually affecting the Treg/Teffector ratio in favor of tumor regression. Moreover, CTX has intrinsic "pro-immunogenic" activities on tumor cells, inducing the hallmarks of immunogenic cell death on a variety of tumor types. Fifty years after its Food and Drug Administration approval, CTX remains a safe and affordable compound endowed with multifaceted properties and plethora of clinical indications. Here we review its immunomodulatory effects and advocate why low dosing CTX could be successfully combined to new-generation cancer vaccines."

Source: Sistigu, A, et al, "Immunomodulatory effects of cyclophosphamide and implementations for vaccine design," Seminars in Immunopathology, July 2011 (abstract)

I do not think anyone looks at alkylators as immunotherapy, even though they are often used before immunontherapy. Allogeneic transplant and CAR T cells ae a couple of examples.

He also pointed out that IMiDs also stimulate T-cell production. That (or some form of T-cell involvement) is more of a key factor that's necessary for "immunotherapy." But in Revlimid's case (and I assume thalidomide and Pomalyst too), according to Dr. Lesokhin, it is not clear how or even whether the stimulated T-cells actually work against myeloma.

Agreed. A myeloma patients immune system has defects and a myeloma patients immune system does not recognize the myeloma as something "foreign" that it should kill. There was a study that showed this previously with regard to NK cells.

"The causes of multiple myeloma (multiple myeloma) remain obscure and there are few known risk factors; however, natural killer T (NKT) cell abnormalities have been reported in patients with multiple myeloma, and therapeutic targeting of NKT cells is promoted as a potential treatment. We characterized NKT cell defects in treated and untreated patients with multiple myeloma and determined the impact of lenalidomide therapy on the NKT cell pool. Lenalidomide is an immunomodulatory drug with co-stimulatory effects on NKT cells in vitro and is an approved treatment for multiple myeloma, although its mode of action in that context is not well defined. We find that patients with relapsed/progressive multiple myeloma had a marked deficiency in NKT cell numbers. In contrast, newly diagnosed patients had relatively normal NKT cell frequency and function prior to treatment, although a specific NKT cell deficiency emerged after high-dose melphalan and autologous stem cell transplantation (ASCT) regimen. This also impacted NK cells and conventional T cells, but the recovery of NKT cells was considerably delayed, resulting in a prolonged, treatment-induced NKT cell deficit. Longitudinal analysis of individual patients revealed that lenalidomide therapy had no in-vivo impact on NKT cell numbers or cytokine production, either as induction therapy, or as maintenance therapy following ASCT, indicating that its clinical benefits in this setting are independent of NKT cell modulation."

Source: Chan, A.C., et al, "Natural killer T cell defects in multiple myeloma and the impact of lenalidomide therapy," Clinical & Experimental Immunology, December 2013 (full text of article)

Now note the difference between myeloma patients that had previously done an allogeneic transplant.

"Lenalidomide may prevent relapses after allogeneic stem cell transplantation by promoting the immune-mediated graft-versus-tumor effect. We performed a prospective phase I/II study to define the dose-limiting toxicity and the immunologic effects of lenalidomide given early (day 100-180) after allograft for four cycles in patients with multiple myeloma. According to the Fibonacci design, 24 patients with a median age of 53 years were included. Dose-limiting toxicity was organ toxicity owing to graft-versus-host disease, and the maximum tolerable dose was 5 mg. The incidence of graft-versus-host disease after lenalidomide was 38%, occurring after a median of 22 days, and was beside organ toxicity, a leading cause to discontinue the study in 29% of the patients. Immune monitoring revealed a significant increase in peripheral γ-interferon-secreting CD4(+) and CD8(+) T cells within the first week of lenalidomide treatment followed by a delayed increase in T regulatory cells. Furthermore, natural killer (NK) cells isolated from the peripheral blood of patients evidenced a significantly improved antimyeloma activity after lenalidomide treatment. The immune effect might have contributed to the increased CR rate from 24-42% after lenalidomide treatment because nonresponding patients showed significantly less natural killer and T cell activation."

Source: Wolschke, C, et al, "Postallograft lenalidomide induces strong NK cell–mediated antimyeloma activity and risk for T cell–mediated GvHD: Results from a phase I/II dose-finding study," Experimental Hematology, February 2013 (abstract)

Hope that helps explain the difference, as I understand it anyway. I think the last 2 studies show the difference between a patient with an immune system that can identify the disease as foreign (allo patient) compared to patients with their own immune system.

Mark

[mikeb]

Re: New York Times article on immunotherapy

by mikeb on Sun Aug 14, 2016 4:30 pm

Hi Mark11,

Thanks for your post. You made a couple of good points!

The cyclophosphamide (Cytoxan) example was a good one. The drugs we take to deal with cancers are classified as alkylators or IMiDs or whatever, but that doesn't tell the whole story because many (most?) of them work through multiple pathways. So the classifications are sort of a convenient way for us to think about them, but it does result in oversimplifying things a bit.

The last two papers showing how auto and allo patients responded differently were interesting too. Very interesting that "resetting" the immune system through an allo transplant enables Revlimid to stimulate NK cell growth, but that an auto transplant does not seem to help much with that.

Mike